[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.
[Show abstract][Hide abstract] ABSTRACT: To investigate efficacy and safety of second-line treatment with irinotecan-loaded drug-eluting beads (DEBIRI) and cetuximab (DEBIRITUX) of unresectable colorectal liver metastases.
Patients with the following characteristics were included in the study: unresectable hepatic metastases from colorectal carcinoma (CRC-LM), progression after first line chemotherapy (any type of chemotherapeutic drug and combination was allowed), second line treatment (mandatory), which included for each patient (unregarding the KRas status) two cycles of DEBIRI (using 100-300 μm beads loaded with irinotecan at a total dose 200 mg) followed by 12 cycles of cetuximab that was administered weekly at a first dose of 400 mg/m(2) and then 250 mg/m(2); good performance status (0-2) and liver functionality (alanine aminotransferase and gamma-glutamyl transferase not exceeding three times the upper limit of normal, total bilirubin not exceeding 2.5 mg/mL). Data were collected retrospectively and included: tumor response (evaluated monthly for 6 mo then every 3 mo), overall response rate (ORR), KRas status, type and intensity of adverse events (G according to the Common Terminology Criteria for Adverse Events v3.0, CTCAE), overall survival (OS) and progression free survival (PFS).
Forty consecutive cases of CRC hepatic metastases were included in the study. Median duration of DEBIRITUX was 4.4 mo (range, 4.0-6.5). Sixteen patients (40%) received the planned 2 cycles of DEBIRI and an average of 10 cetuximab cycles. ORR of the whole sample was 50%, in particular 4 patients were complete responders (10%) and 16 (40%) partial responders. The most observed side effects (G2) were: post-embolization syndrome (30%), diarrhea (25%), skin rushes (38%) and asthenia (35%). The retrospective evaluation of KRas status (24 wild type, 16 mutated) showed that the group of patients with wild type KRas had ORR significantly higher than mutant KRas. Median follow-up was 29 mo (8-48 range); median PFS was 9.8 mo and OS was 20.4 mo. Future randomized trials are required in this setting to establish a role for DEBIRITUX compared with systemic chemotherapy.
DEBIRITUX seems to be efficacious after first line chemotherapy for the treatment of unresectable CRC-LM.
[Show abstract][Hide abstract] ABSTRACT: Chemotherapy near the end of life is an issue frequently discussed nowadays, but literature is generally poor. We analyzed patients with cancer who received chemotherapy in their last month of life.
The study involved all patients treated in our oncological department between 2010 and 2012; our attention focused on patients receiving chemotherapy in their last month of life. The hematologic malignancies are excluded.
During the covered period, 2164 pts received chemotherapy, 162 received chemotherapy in their last month of life (24.3 %). The median age of this subgroup was 67.8 years, and median Eastern Cooperative Oncology Group (ECOG) performance status was 2. One hundred and five patients (64.8 %) were males. All patients presented a metastatic disease. Causes of death are as follows: 64.8 % progressive disease, sudden death in 4.9 %, toxicity in 3.1 %, and not available in 27.2 %.
Twenty-four percent of patients treated with chemotherapy received their last regimen within 1 month of death. Percentage is in line with existing results. It is commonly acknowledged that age, performance status, tumor sensitivity, survival prognosis, and comorbidities should be considered in every chemotherapy decision-making; nevertheless, some studies show that age is not a crucial factor. At present, individual clinician is the only predictor for continuing chemotherapy in the last 4 weeks of life. Although appropriateness criteria were applied, patients were submitted to chemotherapy within 1 month of life; we hope that development of simultaneous care could help in end-life decision-making.
No preview · Article · Apr 2015 · Supportive Care in Cancer
[Show abstract][Hide abstract] ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) patients have the highest risk of developing cachexia, which is a direct cause of reduced quality of life and shorter survival. Novel biomarkers to identify patients at risk of cachexia are needed and might have a substantial impact on clinical management. Here we investigated the prognostic value and association of SELP-rs6136, IL6-rs1800796 and AKT1-rs1130233 polymorphisms with cachexia in PDAC. Genotyping was performed in DNA from blood samples of a test and validation cohorts of 151 and 152 chemo-naive locally-advanced/metastatic PDAC patients, respectively. The association of SELP-rs6136, IL6-rs1800796 and AKT1-rs1130233 polymorphisms with cachexia as well as the correlation between cachexia and the candidate polymorphisms and overall survival were analyzed. Akt expression and phosphorylation in muscle biopsies were evaluated by specific ELISA assays. SELP-rs6136-AA and AKT1-rs1130233-AA/GA genotypes were associated with increased risk of developing cachexia in both cohorts (SELP: p = 0.011 and p = 0.045; AKT1: p = 0.004 and p = 0.019 for the first and second cohorts, respectively), while patients carrying AKT1-rs1130233-GG survived significantly longer (p = 0.002 and p = 0.004 for the first and second cohorts, respectively). In the multivariate analysis AKT1-rs1130233-AA/GA genotypes were significant predictors for shorter survival, with an increased risk of death of 1.7 (p = 0.002) and 1.6 (p = 0.004), in the first and second cohorts, respectively. This might be explained by the reduced phosphorylation of Akt1 in muscle biopsies from patients harboring AKT1-rs1130233-AA/GA (p = 0.003), favoring apoptosis induction. In conclusion, SELP and AKT1 polymorphisms may play a role in the risk of cachexia and death in PDAC patients, and should be further evaluated in larger prospective studies.
[Show abstract][Hide abstract] ABSTRACT: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
[Show abstract][Hide abstract] ABSTRACT: Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is upregulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001 - everolimus - in patients with BTC progressing after prior chemotherapy.
This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in 8 sites in Italy. Patients with locally-advanced, metastatic, or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary endpoints were disease control rate (DCR) and objective response rate (ORR). Secondary endpoints were progression-free-survival (PFS), overall survival (OS) and time-to-progression (TTP).
Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. Median (95% CI) PFS was 3.2 (1.8-4.0) months, and median OS was 7.7 (5.5-13.2) months. Median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events.
Everolimus demonstrated a favourable toxicity profile and encouraging antitumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC.
[Show abstract][Hide abstract] ABSTRACT: Aim:
EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms.
Materials & methods:
EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247).
EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts.
EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC.
No preview · Article · Apr 2014 · Pharmacogenomics
[Show abstract][Hide abstract] ABSTRACT: Aim: EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms. Materials & methods: EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247). Results: EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts. Conclusion: EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC. Original submitted 31 July 2013; Revision submitted 4 November 2013.
No preview · Article · Apr 2014 · Pharmacogenomics
[Show abstract][Hide abstract] ABSTRACT: Cholangiocarcinoma (CCA) is a deadly disease arising from the malignant transformation of cholangiocytes. Enhancer of zeste homolog 2 (EZH2) is overexpressed in poorly differentiated CCA. Functional single nucleotide polymorphisms (SNPs) in this gene may affect the role of EZH2 in cholangiocarcinogenesis and chemoresistance. The aim of the current study was to evaluate the correlation between EZH2 SNPs and clinical outcome. Using PROMO3.0, GeneCard and MicroSNiper, 4 EZH2 SNPs with functional relevance in CCA were selected in silico. These SNPs were studied in genomic DNA extracted from the blood samples of 75 patients with advanced CCA, who were treated with epirubicin-cisplatin-xeloda (ECX regimen). SNP genotyping was performed with specific PCR assays. The rs887569 TT genotype was correlated with a significantly longer overall survival (OS; TT vs. CT-CC, P=0.026). Moreover, the TT genotype revealed a trend toward a significant association with a reduced risk of mortality (HR, 0.59; 95% CI, 0.33-1.05; P=0.075), by multivariate analysis. These results support future studies on the role of rs887569 EZH2 SNP as a possible predictive marker of OS in advanced CCA patients.
[Show abstract][Hide abstract] ABSTRACT: The use of platinated agents in combination chemotherapy regimens for advanced pancreatic cancer is controversial owing to the lack of an outstanding impact on the outcome and a substantial increase in hematologic and extra-hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. The Xeroderma-Pigmentosum group-D polymorphism at codon-751 (XPD-Lys751Gln) emerged as the most significant independent predictor for death- and progression-risk in our previous study on functional polymorphisms in 122 advanced pancreatic cancer patients treated with cisplatin–docetaxel–capecitabine–gemcitabine and cisplatin–epirubicin–capecitabine–gemcitabine (or EC-GemCap). To confirm the prognostic role of this variable, we further evaluated the correlation of XPD-Lys751Gln with outcome in another 125 patients treated with the same regimens, and 90 treated with gemcitabine monotherapy. Genotyping was successfully carried out in the vast majority of DNA samples. Genotype frequencies followed Hardy–Weinberg equilibrium, and XPD-Lys751Gln was associated with differential progression-free and overall-survival. Multivariate analysis confirmed its prognostic significance in platinum-based regimens. In particular, XPD-Gln751Gln was significantly associated with risk of death (hazard ratio, HR = 1.7, 95% confidence interval [CI], 1.1–2.6, p = 0.011) and risk of progression (HR = 1.7, 95% CI, 1.1–2.5, p = 0.013). No correlation was observed in gemcitabine monotherapy-treated patients. The analysis of DNA damage using extra-long-PCR in lymphocytes supported the association of XPD-Gln751Gln with greater resistance to cisplatin-induced damage. The increasing evidence of XPD-Lys751Gln impact on the outcome of gemcitabine–cisplatin-based polychemotherapy leads to plan prospective studies to validate the role of this polymorphism as a new tool for optimization of the currently available treatments in pancreatic cancer.
Full-text · Article · Aug 2013 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Extraneural dissemination of oligodendroglioma is rare. Cases of breast metastases have never been described in the literature.
We report the first two cases of young women with initial diagnosis of anaplastic oligodendroglioma who experienced mammary gland metastases and a review of the literature.
Immunohistochemical analysis performed on material from both primary and metastatic sites did not allow to draw any conclusion on possible etiopathogenetic hypothesis. A review of literature yielded 35 cases of extracranial metastatic oligodendroglioma from 1989 to 2012.
Though rare, extracranial dissemination from oligodendroglioma may occur not only in long surviving heavily pre-treated patients. The review of literature and these two cases suggest that spread is primarily to bone and then from bone to other organs through hematogenous route mostly due to leptomeningeal or dura mater invasion. Chemotherapy regimens similar to those commonly used for non metastatic oligodendroglioma are recommended for patients with good performance status.
No preview · Article · Aug 2013 · Critical reviews in oncology/hematology
[Show abstract][Hide abstract] ABSTRACT: In Italy, data regarding the use of complementary therapies (CTs) among patients with cancer are sparse and discordant.
The present study aimed to investigate the demographic and psychological characteristics of Italian cancer patients who use CTs and the perceived benefit of users.
Eight hundred three patients from six Italian oncology departments were interviewed about CT use and completed two questionnaires to explore psychological distress and the resilience trait called sense of coherence (SOC). Patients included in the study had different primary tumor sites and were in different phases of the disease and care process.
At the time of measurement, 37.9% of patients were using one or more types of CTs. The most commonly used CTs were diets and dietary supplements (27.5%), herbs (10.8%), homeopathy (6.4%), and mind-body therapies (5.5%). The Italian context is characterized by a high percentage of patients who informed their physicians about CT use (66.3%) and who experienced benefits (89.6%); 75.2% of the patients had used CTs in the past. Multivariate analysis revealed that young, female patients, who previously used complementary and alternative medicine in the past, appear more likely to use at least one type of CT in the present. Predictors of the use of CTs varied according to the type of CT. Among psychological factors, SOC was positively associated with both past and present CT use.
Overall prevalence of CTs among Italian cancer patients is high and is in accordance with the European average. In addition to clinical and sociodemographic factors, the resilience trait SOC also was associated with CT use.
No preview · Article · Jul 2013 · Journal of pain and symptom management
[Show abstract][Hide abstract] ABSTRACT: New strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting.
Patients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5mg daily until progression or a maximum of 6months (arm B). The primary outcome measure was the probability of being progression-free at 6months (PFS-6) from randomisation. Assuming P0=10%; P1=30%, α .10; β .10, the target accrual was 26 patients per arm.
28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91days (7-186). Main grade 3-4 toxicity was thrombocytopenia, neutropenia and hand-foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0-10.6%) and 22.2% (95% CI: 6.2-38.2%; P<0.01); 2y overall survival was 7.1% (95% CI: 0-16.8%) and 22.9% (95% CI: 5.8-40.0%; P=0.11), stable disease 21.4% and 51.9% (P=0.02).
This is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population.
No preview · Article · Jul 2013 · European journal of cancer (Oxford, England: 1990)